The candidate, Simon D. Spivack, MD, MPH, is an academic pulmonary physician with demonstrated interest and background in experimental and clinical environmentally-induced lung disease, molecular biology, toxicology and epidemiology. the candidate views the K08 Mentored Clinical Scientist Development Award as facilitating his immediate career goal of developing into an independent investigator in the field of molecular epidemiology as it relates to lung cancer. Long-term career goals are to address major issues related to the environment-human lung interface, combining molecular genetic, clinical and epidemiologic perspectives, in the context of an academic medicine and public health career. the environment for the K08 proposal includes the Laboratory of Human Toxicology & Molecular Epidemiology, Wadsworth Center of the New York State Department of Health, the supporting departments of epidemiology, biostatistics, molecular genetics, biological imaging, the SUNY School of Public Health, and the clinical and pathological resources of the Albany Medical College and Veterans Administration Hospitals. The research project is aimed at defining individual genetic susceptibility factors that confer risk for lung cancer, in a manner applicable to broad-based lung cancer screening programs. The phase I and phase II enzymes responsible for activation of tobacco-smoke constituents to carcinogens, and their coordinate deactivation, display polymorphism across individuals, and are reasonable candidate biomarkers associated with individual lung cancer susceptibility. First, the utility of easily-accessed surrogate tissues as substitutes for target lung tissue will be examined as they reflect molecular events in lung carcinogenesis. Procarcinogen metabolizing polymorphisms and biomarkers of DNA damage will be assessed in human lung, nasal epithelium and peripheral lymphocytes from the same individual. Second, biomarkers measured in surrogate tissue will be validated as lung cancer susceptibility markers by correlation with the presence or absence of lung cancer in an individual, in a case-control design. Therefore, this project will valuate the feasibility of molecular screening in lung cancer.